Claims
- 1. A compound of the formula (A) or a pharmaceutically acceptable salt thereof: ##STR48## and when R.sup.2 =OH then Y may also be ##STR49## wherein n=0,1;
- R.sup.1 =H or deuterium;
- R.sup.2 =OR.sup.4 or NHOH;
- R.sup.4 =H, alkyl, cycloalkyl or aralkyl;
- R.sup.3 =H, (CR.sup.8 R.sup.9).sub.0-6 CF.sub.3, (CR.sup.8 R.sup.9).sub.0-6 CF.sub.2 CF.sub.3, (CR.sup.8 R.sup.9).sub.0-6 COOR.sup.5, (CR.sup.8 R.sup.9).sub.0-6 CONR.sup.6 R.sup.7, CF.sub.2 (CR.sup.8 R.sup.9).sub.0-6 aryl, CF.sub.2 (CR.sup.8 R.sup.9).sub.0-6 heteroaryl, CF.sub.2 (CR.sup.8 R.sup.9).sub.0-6 alkyl, CHN.sub.2, CH.sub.2 R.sup.10 or COR.sup.5 ;
- wherein
- R.sup.5 =H, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl;
- R.sup.6 and R.sup.7 are independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl and where R.sup.6 and R.sup.7 are taken together may be a 3-,4-,5-,6- or 7-membered carbocyclic ring;
- R.sup.8 and R.sup.9 are independently H, or alkyl;
- R.sup.10 =alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, H, halo, SR.sup.5, SR.sup.5 R.sup.6, O(CO).sub.0-1 aryl, O(CO).sub.0-1 heteroaryl, OP(O)R.sup.11 R.sup.12, ##STR50## R.sup.11 and R.sup.12 are selected from the group consisting of H, OH, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkoxy, aroxy, aralkyloxy, heteroaroxy and heteroaralkyloxy;
- R.sup.13 =H, alkyl, aryl or aralkyl;
- R.sup.14 and R.sup.15 are selected from the group consisting of H, alkyl and aryl, or when taken together R.sup.14 and R.sup.15 is an aryl ring;
- X.sup.1 =O, S or NR.sup.28 where R.sup.28 =H, alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl;
- R.sup.16 =H, Cl, alkyl or (CR.sup.8 R.sup.9).sub.0-6 -aryl;
- R.sup.17 and R.sup.18 are independently H or alkyl;
- X.sup.2 =CH.sub.2, O or NR.sup.28 ;
- R.sup.19 =H, alkyl, cycloalkyl, alkylcycloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl;
- R.sup.20 =H, alkyl, CF.sub.3, CF.sub.2 CF.sub.3, COOR.sup.5, CONR.sup.6 R.sup.7, cycloalkyl, alkylcycloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl;
- R.sup.22, R.sup.23, R.sup.24, R.sup.25, R.sup.26, and R.sup.27 are selected from the group consisting of H, alkyl, cycloalkyl, alkylcycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl and R.sup.29 ; and where R.sup.24 and R.sup.25 when taken together may be aryl or heteroaryl;
- X.sup.3 =O or S;
- R.sup.29 =F, Cl, CF.sub.3, CF.sub.2 CF.sub.3, (CF.sub.2).sub.0-3 --H, COOR.sup.5 or CONR.sup.30 R.sup.31, where R.sup.30 and R.sup.31 are selected from the group consisting of R.sup.6, R.sup.7, ##STR51## wherein q=0 or 1;
- m=0, 1, 2 or 3;
- m=0, 1, 2 or 3;
- o=0, 1 or 2;
- X.sup.4 =H or alkylthio; ##STR52## R.sup.33 and R.sup.34 are selected from the group consisting of alkyl, aryl or when taken together, R.sup.33 and R.sup.34 are aryl, heteroaryl, or a double bond;
- R.sup.35 and R.sup.36 are an oxygen atom;
- R.sup.37 =H or alkyl;
- R.sup.38 is selected from the group consisting of H, alkyl, aryl, aralky, heteroaryl, heteroaralkyl, R.sup.40 --SO.sub.2, R.sup.41 --CO, R.sup.50 O--CO and R.sup.51 NR.sup.5 --CO;
- wherein R.sup.40 =R.sup.5 or HNR.sup.5 ;
- R.sup.41 =alkenyl, aralkenyl, heteroaralkenyl, alkynyl, aralkynyl, heteroaralkynyl, R.sup.42 --OCOR.sup.5, R.sup.43 --COR.sup.5, R.sup.42 --NR.sup.47 C(.dbd.NR.sup.6)R.sup.5, R.sup.42 --NR.sup.47 (.dbd.NR.sup.6)NR.sup.5, R.sup.42 --SR.sup.5, R.sup.42 --S(CR.sup.8 R.sup.9).sub.1-6 COOR.sup.47, R.sup.42 --S(CR.sup.8 R.sup.9).sub.1-6 COONR.sup.47 R.sup.48, R.sup.42 --OR.sup.5, R.sup.42 --O(CR.sup.8 R.sup.9).sub.1-6 COOR.sup.47, R.sup.42 --O(CR.sup.8 R.sup.9).sub.1-6 COONR.sup.47 R.sup.48, R.sup.42 --NR.sup.5 SO.sub.2 R.sup.6, R.sup.43 --R.sup.44, R.sup.43 --R.sup.45, R.sup.43 --R.sup.46, R.sup.43 --NR.sup.47 R.sup.48, R.sup.42 --OH or R.sup.43 --CF.sub.3 ;
- wherein R.sup.42 =(CR.sup.8 R.sup.9).sub.1-7 and R.sup.43 =(CR.sup.8 R.sup.9).sub.0-6 ;
- R44=H, alkyl, --(CH.sub.2)0-4-cycloalkyl, ##STR53## aryl, heteroaryl, aralkyl, heteroaralkyl or --(CH.sub.2).sub.2-6 --R.sup.49 ;
- wherein p=1-4;
- R.sup.49 =alkoxy, CH.sub.2 F, CHF.sub.2, CF.sub.3, CF.sub.2 CF.sub.3, OH, COOR.sup.47, CONR.sup.47 R.sup.48, or NR.sup.47 R.sup.48 ;
- wherein R.sup.48 is H, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, CH.sub.2 CH.sub.2 O-alkyl or C(O)--R.sup.49 ;
- R.sup.47 is H, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl;
- and when R.sup.47 and R.sup.48 are taken together, they can equal a five, six or seven membered ring of the type: ##STR54## where p=1-4 and n=0-1; R.sup.49 is alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; ##STR55## where p=1-4; R.sup.50 and R.sup.51 are independently selected from the group consisting of alkyl, R.sup.43 -cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, R.sup.42 -alkenyl, R.sup.42 -heteroaralkenyl, R.sup.42 -alkynyl, R.sup.42 -aralkynyl, R.sup.42 -heteroaralkynyl, R.sup.43 --R.sup.46, R.sup.42 --R.sup.49, R.sup.52 --R.sup.45, R.sup.42 --COOR.sup.47, R.sup.42 --CONR.sup.47 R.sup.48, R.sup.52 --OCOR.sup.5, R.sup.52 --COR.sup.5, R.sup.52 --NR.sup.47 C(.dbd.NR.sup.6)R.sup.5, R.sup.52 --NR.sup.47 (.dbd.NR.sup.6)NR.sup.5, R.sup.52 --SR.sup.5, R.sup.52 --S(CR.sup.8 R.sup.9).sub.1-6 COOR.sup.47, R.sup.52 --S(CR.sup.8 R.sup.9).sub.1-6 COONR.sup.47 R.sup.48, R.sup.52 --OR.sup.5, R.sup.52 --O(CR.sup.8 R.sup.9).sub.1-6 COOR.sup.47, R.sup.52 --O(CR.sup.8 R.sup.9).sub.1-6 COONR.sup.47 R.sup.48, R.sup.52 --NR.sup.5 SO.sub.2 R.sup.6, R.sup.52 --R.sup.44 and R.sup.52 --NR.sup.47 R.sup.48,
- where R.sup.52 =(CR.sup.8 R.sup.9).sub.2-6.
- 2. The compound according to claim 1 wherein:
- R.sup.2 =OR.sup.4 ;
- R.sup.3 =H, COR.sup.5, COOR.sup.5, CONR.sup.6 R.sup.7, CF.sub.2 (CR.sup.8 R.sup.9).sub.0-6 aryl, CF2(CR.sup.8 R.sup.9).sub.0-6 heteroaryl, CF.sub.2 (CR.sup.8 R.sup.9).sub.0-6 alkyl, CHN.sub.2 or CH.sub.2 R.sup.10.
- 3. The compound according to claim 2 wherein:
- R.sup.10 is =alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, O(CO).sub.0-1 aryl, O(CO).sub.0-1 heteroaryl, OP(O)R.sup.11 R.sup.12, ##STR56##
- 4. The compound according to claim 3 wherein:
- R.sup.10 =halo, O(CO).sub.0-1 aryl, OCO-heteroaryl, OP(O)R.sup.10 R.sup.12, ##STR57## where R.sup.11 and R.sup.12 are independently alkyl, aralkyl or aryl; R.sup.19 =aryl; R.sup.20 =alkyl, CF.sub.3, CF.sub.2 CF.sub.3, COOR.sup.8 or CONR.sup.6 R.sup.7 ; R.sup.22 =aryl, aralkyl, heteroaryl or heteroaralkyl.
- 5. The compound according to claim 1 wherein: ##STR58## where X.sup.3 =O; q=0 or 1; m=1 or 2; O=1; R.sup.33 and R.sup.34 when taken together may be aryl or a double bond and where R.sup.37 =H.
- 6. The compound according to claim 2 wherein: ##STR59## where X.sup.3 =O; q=0 or 1; m=1 or 2; O=1; R.sup.33 and R.sup.34 when taken together may be aryl or a double bond and where R.sup.37 =H.
- 7. The compound according to claim 3 wherein: ##STR60## where X.sup.3 =O; q=0 or 1; m=1 or 2; O=1; R.sup.33 and R.sup.34 when taken together may be aryl or a double bond and where R.sup.37 =H.
- 8. The compound according to claim 4 wherein: ##STR61## where X.sup.3 =O; q=0 or 1; m=1or 2; O=1; R.sup.33 and R.sup.34 when taken together may be aryl or a double bond and where R.sup.37 =H.
- 9. The compound according to claim 2 wherein:
- R.sup.4 =H or alkyl;
- R.sup.3 =H or CH.sub.2 R.sup.10 ;
- R.sup.10 =halo, OCO-aryl or ##STR62## R.sup.19 =aryl; R.sup.20 =alkyl, CF.sub.3 or CF.sub.2 CF.sub.3 ; R.sup.21 =H; ##STR63## where X.sup.3 =O; q=0 or 1; m=1 or 2; O=1; R.sup.33 and R.sup.34 when taken together may be aryl or a double bond and where R.sup.37 =H.
- 10. The compound according to claim 9 wherein: ##STR64## m=1 or 2; X.sup.3 =O; and q=0 or 1.
- 11. The compound according to claim 9 wherein: ##STR65## X.sup.3 =O; m=1 or 2; and q=0 or 1.
- 12. The compound according to claim 9 wherein: ##STR66## X.sup.3 =; m=1 or 2; and q=0 or 1.
- 13. The compound according to claim 10 wherein: ##STR67## R.sup.4 =H or alkyl; n=0; R.sup.3 =H, CH.sub.2 -halo, CH.sub.2 --OCO-aryl, or ##STR68## wherein R.sup.21 =H or alkyl.
- 14. The compound according to claim 13 wherein: ##STR69## X.sup.3 =O; m=1 or 2; and q=0 or 1.
- 15. A method for inhibiting interleukin-1.beta. protease activity in a mammal in need of treatment for inflammatory and immune-based diseases of lung, central nervous system, and connective tissue comprising administering to said mammal an effective interleukin-1.beta. inhibitory amount of a composition comprising a compound selected from the group consisting of:
- [9-(Benzyloxycarbonylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid aldehyde;
- [9-Benzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid aldehyde;
- [9-(4-Carboxymethoxybenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid aldehyde;
- [9-(2-Fluorobenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid aldehyde;
- [9-(2-Pyridinoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid aldehyde; and
- [9-(N-4-Methylpiperazinomethylbenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid aldehyde.
- 16. The compound according to claim 1 selected from the group consisting of:
- [9-(Benzyloxycarbonylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone;
- [9-(4-Dimethylaminomethylbenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone;
- [9-(N-[4-Methylpiperazinomethyl]benzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone;
- [9-(4-(N-Methylpiperazinylmethyl)benzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyl-oxymethyl ketone; and
- [9-(4-(N-(2-Methyl)imidazolylmethyl)benzoylamino)octahydro-6,10-dioxo-6H-pyridazino [1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone.
- 17. The compound according to claim 1 selected from the group consisting of:
- [9-(5-Benzimidazoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone;
- [9-(5-Bentriazoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone;
- [9-(N-Carboethoxy-5-bentriazoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone;
- [9-(N-Carboethoxy-5-benzimidazoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone; and
- [9-(Benzyloxycarbonylamino)octahydro-10-oxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone.
- 18. The compound according to claim 1 selected from the group consisting of:
- [9-(4-Dimethylaminomethylbenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl) pyrazoloxymethyl ketone;
- [9-(Benzyloxycarbonylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-phenyl-3-trifluoromethyl) pyrazoloxymethyl ketone;
- [9-(Benzyloxycarbonylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl)pyrazoloxymethyl ketone;
- [9-(Benzyloxycarbonylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(2-pyridinyl)-3-trifluoromethyl)pyrazoloxymethyl ketone; and
- [9-(Benzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl)pyrazoloxymethyl ketone.
- 19. The compound according to claim 1 selected from the group consisting of:
- [9-(4-Carboxymethylthiobenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl) pyrazoloxymethyl ketone;
- [9-(4-Carboxyethylthiobenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl)pyrazoloxymethyl ketone;
- [9-(Isobutyloxycarbonylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl)pyrazoloxymethyl ketone;
- [9-(4-Carboxyethylbenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl)-pyrazoloxymethyl ketone;
- [9-(4-Carboxypropylbenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl) pyrazoloxymethyl ketone;
- [9-(Benzyloxycarbonylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chloro-2-pyridinyl)-3-trifluoromethyl) pyrazoloxymethyl ketone; and
- [9-(4-Dimethylaminomethylbenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(2-pyridinyl)-3-trifluoromethyl)pyrazoloxymethyl ketone.
- 20. The compound according to claim 1 selected from the group consisting of:
- [9-(Benzyloxycarbonylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid aldehyde;
- [9-(Benzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid aldehyde;
- [9-(4-Carboxymethoxybenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid aldehyde;
- [9-(2-Fluorobenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid aldehyde;
- [9-(2-Pyridinoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid aldehyde; and
- [9-(N-4-Methylpiperazinomethylbenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid aldehyde.
- 21. A pharmaceutical composition for inhibiting interleukin-1.beta. protease comprising a compound of the formula (A) defined in claim 1, in a pharmaceutically acceptable carrier.
- 22. A pharmaceutical composition comprising the compound defined in any of claims 2-15, in a pharmaceutically acceptable carrier.
- 23. A pharmaceutical composition comprising the compound according to claim 1 selected from the group consisting of:
- [9-(Benzyloxycarbonylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone;
- [9-(4-Dimethylaminomethylbenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone;
- [9-(N-[4-Methylpiperazinomethyl]benzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone;
- [9-(4-(N-Methylpiperazinylmethyl)benzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyl-oxymethyl ketone; and
- [9-(4-(N-(2-Methyl)imidazolylmethyl)benzoylamino)octahydro-6,10-dioxo-6H-pyridazino [1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone.
- 24. A pharmaceutical composition comprising the compound according to claim 1 selected from the group consisting of:
- [9-(5-Benzimidazoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone;
- [9 -(5-Bentriazoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone;
- [9-(N-Carboethoxy-5-bentriazoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone;
- [9-(N-Carboethoxy-5-benzimidazoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone; and
- [9-(Benzyloxycarbonylamino)octahydro-10-oxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone.
- 25. A pharmaceutical composition comprising the compound according to claim 1 selected from the group consisting of:
- [9-(4-Dimethylaminomethylbenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl) pyrazoloxymethyl ketone;
- [9-(Benzyloxycarbonylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-phenyl-3-trifluoromethyl) pyrazoloxymethyl ketone;
- [9-(Benzyloxycarbonylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl)pyrazoloxymethyl ketone;
- [9-(Benzyloxycarbonylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(2-pyridinyl)-3-trifluoromethyl)pyrazoloxymethyl ketone; and
- [9-(Benzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl)pyrazoloxymethyl ketone.
- 26. A pharmaceutical composition comprising the compound according to claim 1 selected from the group consisting of:
- [9-(4-Carboxymethylthiobenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl) pyrazoloxymethyl ketone;
- [9-(4-Carboxyethylthiobenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5 -(1-(4-chlorophenyl)-3-trifluoromethyl)pyrazoloxymethyl ketone;
- [9-(Isobutyloxycarbonylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl)pyrazoloxymethyl ketone;
- [9-(4-Carboxyethylbenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl)-pyrazoloxymethyl ketone;
- [9-(4-Carboxypropylbenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl) pyrazoloxymethyl ketone;
- [9-(Benzyloxycarbonylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chloro-2-pyridinyl)-3-trifluoromethyl) pyrazoloxymethyl ketone; and
- [9-(4-Dimethylaminomethylbenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(2-pyridinyl)-3-trifluoromethyl)pyrazoloxymethyl ketone.
- 27. A pharmaceutical composition comprising the compound according to claim 1 selected from the group consisting of:
- [9-(Benzyloxycarbonylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid aldehyde;
- [9-(Benzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L- aspartic acid aldehyde;
- [9-(4-Carboxymethoxybenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid aldehyde;
- [9-(2-Fluorobenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid aldehyde;
- [9-(2-Pyridinoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid aldehyde; and
- [9-(N-4-Methylpiperazinomethylbenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid aldehyde.
- 28. A method for inhibiting interleukin-1.beta. protease activity in a mammal in need of treatment for inflammatory and immune-based diseases of lung, central nervous system, and connective tissue comprising administering to said mammal an effective interleukin-1.beta. inhibitory amount of a composition comprising a compound of the formula (A) or a pharmaceutically acceptable salt thereof: ##STR70## and when R.sup.2 =OH then Y can also be equal to: ##STR71## wherein n=0,1;
- R.sup.1 =H or deuterium;
- R.sup.2 =OR.sup.4 or NHOH;
- R.sup.4 =H, alkyl, cycloalkyl, aralkyl;
- R.sup.3 =H, (CR.sup.8 R.sup.9).sub.0-6 CF.sub.3, (CR.sup.8 R.sup.9).sub.0-6 CF.sub.2 CF.sub.3, (CR.sup.8 R.sup.9).sub.0-6 COOR.sup.5, (CR.sup.8 R.sup.9).sub.0-6 CONR.sup.6 R.sup.7, CF.sub.2 (CR.sup.8 R.sup.9).sub.0-6 aryl, CF.sub.2 (CR.sup.8 R.sup.9).sub.0-6 heteroaryl, CF.sub.2 (CR.sup.8 R.sup.9).sub.0-6 alkyl, CHN.sub.2,CH.sub.2 R.sup.10, COR.sup.5 ;
- wherein
- R.sup.5 =H, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl;
- R.sup.6 and R.sup.7 are independently selected from H, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl and where R.sup.6 and R.sup.7 are taken together can be a 3-,4-,5-,6- or 7-membered carbocyclic ring;
- R.sup.8 and R.sup.9 are independently H, or alkyl;
- R.sup.10 =alkyl, aryl, aralkyl, heteroaryl, heteroarakyl, H, halo, SR.sup.5, SR.sup.5 R.sup.6, O(CO).sub.0-1 aryl, O(CO).sub.0-1 heteroaryl, OP(O)R.sup.11 R.sup.12, ##STR72## R.sup.11 and R.sup.12 are optionally selected from H, OH, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkoxy, aroxy, aralkyloxy, heteroaroxy, heteroaralkyloxy;
- R.sup.13 =H, alkyl, aryl, aralkyl;
- R.sup.14 and R.sup.15 are optionally selected from H, alkyl, aryl, or when taken together R.sup.14 and R.sup.15 is an aryl ring;
- X.sup.1 =O, S, NR.sup.28 where R.sup.28 =H, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl;
- R.sup.16 =H, Cl, alkyl, (CR.sup.8 R.sup.9).sub.0-6 -aryl;
- R.sup.17 and R.sup.18 are independently H or alkyl;
- X.sup.2 =CH.sub.2, O, NR.sup.28 ;
- R.sup.19 =H, alkyl, cycloalkyl, alkylcycloalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl;
- R.sup.20 =H, alkyl, CF.sub.3, CF.sub.2,CF.sub.3, COOR.sup.5, CONR.sup.6 R.sup.7, cycloalkyl, alkylcycloalkyl, aryl, aralkyl, heteroaralkyl, heteroaryl and where R.sup.21 =H or alkyl;
- R.sup.22, R.sup.23, R.sup.24, R.sup.25, R.sup.26, and R.sup.27 are independently selected from H, alkyl, cycloalkyl, alkylcycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl and R.sup.29 ; and where R.sup.24 and R.sup.25 when taken together may be aryl or heteroaryl;
- X.sup.3 =O,S;
- R.sup.29 =F, Cl, CF.sub.3, CF.sub.2 CF.sub.3, (CF.sub.2).sub.0-3 --H, COOR.sup.5, CONR.sup.30 R.sup.31, where R.sup.30 and R.sup.31 are optionally selected from R.sup.6 and R.sup.7, ##STR73## wherein q=0,1;
- m=0,1,2,3;
- o=0,1,2;
- X.sup.4 =H, alkylthio; ##STR74## R.sup.33 and R.sup.34 are optionally H, alkyl, aryl or when taken together, R.sup.33 and R.sup.34 are aryl, heteroaryl, or a double bond;
- R.sup.35 and R.sup.36 are optionally an oxygen atom or no bond;
- R.sup.37 =H, alkyl;
- R.sup.38 =independently selected from H, alkyl, aryl, aralky, heteroaryl, heteroaralkyl, R.sup.40 --SO.sub.2, R.sup.41 --CO, R.sup.50 O--CO, R.sup.51 NR.sup.5 --CO;
- wherein R.sup.40 =R.sup.5 or HNR.sup.5 ;
- R.sup.41 =alkenyl, aralkenyl, heteroaralkenyl, alkynyl, aralkynyl, heteroaralkynyl, R.sup.42 --OCOR.sup.5, R.sup.43 --COR.sup.5, R.sup.42 --NR.sup.47 C(.dbd.NR.sup.6)R.sup.5, R.sup.42 --NR.sup.47 (.dbd.NR.sup.6)NR.sup.5, R.sup.42 --SR.sup.5, R.sup.42 --S(CR.sup.8 R.sup.9).sub.1-6 COOR.sup.47, R.sup.42 --S(CR.sup.8 R.sup.9).sub.1-6 COONR.sup.47 R.sup.48, R.sup.42 --OR.sup.5, R.sup.42 --O(CR.sup.8 R.sup.9).sub.1-6 COOR.sup.47, R.sup.42 --O(CR.sup.8 R.sup.9).sub.1-6 COONR.sup.47 R.sup.48, R.sup.42 --NR.sup.5 SO.sub.2 R.sup.6, R.sup.43 --R.sup.44, R.sup.43 --R.sup.45, R.sup.43 --R.sup.46, R.sup.43 --NR.sup.47 R.sup.48, R.sup.42 --OH, R.sup.43 --CF.sub.3 ;
- wherein R.sup.42 =(CR.sup.8 R.sup.9).sub.1-7 and R.sup.43 =(CR.sup.8 R.sup.9).sub.0-6 ;
- R.sup.44 =H, alkyl, --(CH.sub.2).sub.0-4 -cycloalkyl; ##STR75## aryl, heteroaryl, aralkyl, heteroaralkyl, --(CH.sub.2).sub.2-6 --R.sup.49 ; wherein p=1-4;
- R.sup.49 =alkoxy, CH.sub.2 F, CHF.sub.2, CF.sub.3, CF.sub.2 CF.sub.3, OH, COOR.sup.47, CONR.sup.47 R.sup.48, or NR.sup.47 R.sup.48 ;
- wherein R.sup.48 is independently H, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, CH.sub.2 CH.sub.2 O-alkyl and C(O)--R.sup.49 ;
- R.sup.47 is independently H, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl;
- and when R.sup.47 and R.sup.48 are taken together, they can equal a five, six or seven membered ring of the type: ##STR76## where p=1-4 and n=0-1; R.sup.49 is alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl; ##STR77## where p=1-4; R.sup.50 and R.sup.51 =independently selected from alkyl, R.sup.43 -cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, R.sup.42 -alkenyl, R.sup.42 -heteroaralkenyl, R.sup.42 -alkynyl, R.sup.42 -aralkynyl, R.sup.42 -heteroaralkynyl, R.sup.43 --R.sup.46, R.sup.42 --R.sup.49, R.sup.52 --R.sup.45, R.sup.42 --COOR.sup.47, R.sup.42 --CONR.sup.47 R.sup.48, R.sup.52 --OCOR.sup.5, R.sup.52 --COR.sup.5, R.sup.52 --NR.sup.47 C(.dbd.NR.sup.6)R.sup.5, R.sup.52 --NR.sup.47 (.dbd.NR.sup.6)NR.sup.5, R.sup.52 --SR.sup.5, R.sup.52 --S(CR.sup.8 R.sup.9).sub.1-6 COOR.sup.47, R.sup.52 --S(CR.sup.8 R.sup.9).sub.1-6 COONR.sup.47 R.sup.48, R.sup.52 --OR.sup.5, R.sup.52 --O(CR.sup.8 R.sup.9).sub.1-6 COOR.sup.47, R.sup.52 --O(CR.sup.8 R.sup.9).sub.1-6 COONR.sup.47 R.sup.48, R.sup.52 --NR.sup.5 SO.sub.2 R.sup.6, R.sup.52 --R.sup.44, R.sup.52 --NR.sup.47 R.sup.48,
- where R.sup.52 =(CR.sup.8 R.sup.9).sub.2-6.
- 29. A method for inhibiting interleukin-1.beta. protease activity in a mammal in need of treatment for inflammatory and immune-based diseases of lung, central nervous system, and connective tissue comprising administering to said mammal an effective interleukin-1.beta. inhibitory amount of a composition comprising a compound defined in any of claims 2-15.
- 30. A method for inhibiting interleukin-1.beta. protease activity in a mammal in need of treatment for inflammatory and immune-based diseases of lung, central nervous system, and connective tissue comprising administering to said mammal an effective interleukin-1.beta. inhibitory amount of a composition comprising a compound selected from the group consisting of:
- [9-(Benzyloxycarbonylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone;
- [9-(4-Dimethylaminomethylbenzylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone;
- [9-(N-[4-Methylpiperazinomethyl]benzylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone;
- [9-(4-(N-Methylpiperazinylmethyl)benzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyl-oxymethyl ketone; and
- [9-(4-(N-(2-Methyl)imidazolylmethyl)benzoylamino)octahydro-6,10-dioxo-6H-pyridazino [1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone.
- 31. A method for inhibiting interleukin-1.beta. protease activity in a mammal in need of treatment for inflammatory and immune-based diseases of lung, central nervous system, and connective tissue comprising administering to said mammal an effective interleukin-1.beta. inhibitory amount of a composition comprising a compound selected from the group consisting of:
- [9-(5-Benzimidazoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone;
- [9-(5-Bentriazoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone;
- [9-(N-Carboethoxy-5-bentriazoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone;
- [9-(N-Carboethoxy-5-benzimidazoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone; and
- [9-(Benzyloxycarbonylamino)octahydro-10-oxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone.
- 32. A method for inhibiting interleukin-1.beta. protease activity in a mammal in need of treatment for inflammatory and immune-based diseases of lung, central nervous system, and connective tissue comprising administering to said mammal an effective interleukin-1.beta. inhibitory amount of a composition comprising a compound selected from the group consisting of:
- [9-(4-Dimethylaminomethylbenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl) pyrazoloxymethyl ketone;
- [9-(Benzyloxycarbonylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-phenyl-3-trifluoromethyl) pyrazoloxymethyl ketone;
- [9-(Benzyloxycarbonylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl)pyrazoloxymethyl ketone;
- [9-(Benzyloxycarbonylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(2-pyridinyl)-3-trifluoromethyl)pyrazoloxymethyl ketone; and
- [9-(Benzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl)pyrazoloxymethyl ketone.
- 33. A method for inhibiting interleukin-1.beta. protease activity in a mammal in need of treatment for inflammatory and immune-based diseases of lung, central nervous system, and connective tissue comprising administering to said mammal an effective interleukin-1.beta. inhibitory amount of a composition comprising a compound selected from the group consisting of:
- [9-(4-Carboxymethylthiobenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl) pyrazoloxymethyl ketone;
- [9-(4-Carboxyethylthiobenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl)pyrazoloxymethyl ketone;
- [9-(Isobutyloxycarbonylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl)pyrazoloxymethyl ketone;
- [9-(4-Carboxyethylbenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl)-pyrazoloxymethyl ketone;
- [9-(4-Carboxypropylbenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl) pyrazoloxymethyl ketone;
- [9-(Benzyloxycarbonylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(4-chloro-2-pyridinyl)-3-trifluoromethyl) pyrazoloxymethyl ketone; and
- [9-(4-Dimethylaminomethylbenzoylamino)octahydro-6,10-dioxo-6H-pyridazino[1,2a][1,2]diazepine-1-formoyl]-L-aspartic acid 5-(1-(2-pyridinyl)-3-trifluoromethyl)pyrazoloxymethyl ketone.
Parent Case Info
This application is a division of application Ser. No. 08/255,276, filed Jun. 8, 1994, now U.S. Pat. No. 5,552,400.
US Referenced Citations (3)
Number |
Name |
Date |
Kind |
4341781 |
Hassall et al. |
Jul 1982 |
|
4399136 |
Hassall et al. |
Aug 1983 |
|
4988771 |
Angebauer et al. |
Jan 1991 |
|
Divisions (1)
|
Number |
Date |
Country |
Parent |
255276 |
Jun 1994 |
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